Abstract
The NLRP3 inflammasome is a multiprotein oligomer responsible for activation of the inflammatory response by promoting the maturation and secretion of the pro-inflammatory cytokines IL-1β and IL-18. Dysregulation of this inflammasome has been linked to several autoimmune diseases, indicating that NLRP3 is tightly regulated to prevent aberrant activation. The regulation of NLRP3 activation remains unclear. Here, we report the identification of vitamin D receptor (VDR) as a negative regulator of NLRP3 oligomerization and activation. VDR can physically bind NLRP3 and block the association of NLRP3 with BRCC3. When BRCC3-mediated deubiquitination of NLRP3 is inhibited by VDR, NLRP3 activation is subsequently inhibited. In the absence of VDR, caspase-1 activation and IL-1β release are increased in response to LPS-induced inflammation or alum-induced peritoneal inflammation, indicating that VDR is a negative regulator of NLRP3 inflammasome activation in vivo. In addition, vitamin D negatively regulates the NLRP3 inflammasome via VDR signaling to effectively inhibit IL-1β secretion. These studies demonstrate that VDR signaling constrains NLRP3 inflammasome activation and might be a potential treatment target for NLRP3 inflammasome-related diseases.
Highlights
Pyroptosis is a highly inflammatory form of programmed cell death that promotes the rapid clearance of various bacterial and virus infections
vitamin D receptor (VDR) directly interacts with NLRP3 and disturbs the association of NLRP3 with BRCC3, thereby inhibiting the deubiquitination of NLRP3 by BRCC3 and subsequently blocking activation of the NLRP3 inflammasome
Interactions were observed between HA-VDR and full-length NLRP3 and NLRP3 mutated in the carboxy-terminal leucine-rich repeat (LRR) domain and nucleotide-binding domain (NACHT), while NLRP3 mutated in the amino-terminal pyrin domain (PYD) showed no interaction with HA-VDR (Figure 1F)
Summary
Pyroptosis is a highly inflammatory form of programmed cell death that promotes the rapid clearance of various bacterial and virus infections. VDR Inhibits NLRP3 Activation (IBD), gouty arthritis, multiple sclerosis, and vitiligo, as well as auto-inflammatory disorders [5,6,7,8] These diseases and disorders have been connected to the increased or decreased secretion of pro-inflammatory cytokines regulated by the inflammasome, indicating that NLRP3 inflammasome activation is tightly controlled in the normal state. Vitamin D and VDR have anti-inflammatory effects and play an immunosuppressive role in autoimmunity Together, they increase the phagocytic ability of monocytes to modulate the innate immune system [16, 17] and promote the ability of dendritic cells to modulate regulatory T cell differentiation [12, 14, 18, 19]. VDR directly interacts with NLRP3 and disturbs the association of NLRP3 with BRCC3, thereby inhibiting the deubiquitination of NLRP3 by BRCC3 and subsequently blocking activation of the NLRP3 inflammasome
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